Scalable polypropionate lactone stereotetrads

ABSTRACT

The present technology is directed to polypropionate lactone stereotetrads of Formula (I) (or a pharmaceutically acceptable salt and/or solvate thereof) which are significant intermediates for multiple synthetic applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application of PCT/US2017/065652,filed Dec. 11, 2017, which claims priority to U.S. ProvisionalApplication No. 62/497,952, filed Dec. 9, 2016, the contents of each ofwhich are incorporated herein by reference in their entirety for any andall purposes.

FIELD

The present technology is directed to polypropionate lactonestereotetrads as valuable tools for multiple synthetic applications.

SUMMARY

In an aspect, a compound according to Formula I is provided

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

-   -   R¹ is H, trimethylsilyl, triethylsilyl,        tert-butyl-dimethylsilyl, triisopropylsilyl,        tert-butyl-diphenylsilyl, triphenylsilyl, dimethylphenylsilyl,        methyldiphenylsilyl, acetyl, pivaloyl, trichloroacetyl,        2,2,2-trichloroethoxycarbonyl, benzyl, p-methoxybenzyl,        3-(phenyl sulfonyl)propionyl, tosyl, or mesyl;    -   R² is H, trimethylsilyl, triethylsilyl,        tert-butyl-dimethylsilyl, triisopropylsilyl,        tert-butyl-diphenylsilyl, triphenylsilyl, dimethylphenylsilyl,        methyldiphenylsilyl, acetyl, pivaloyl, trichloroacetyl,        2,2,2-trichloroethoxycarbonyl, benzyl, p-methoxybenzyl,        3-(phenylsulfonyl)propionyl, tosyl, or mesyl; and    -   n is 1 or 2;

provided that the compound of Formula I is not:

DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a photograph of crystals of an embodiment of the presenttechnology, according to the working examples.

FIG. 2 provides a photograph of crystals of another embodiment of thepresent technology, according to the working examples.

DETAILED DESCRIPTION

The following terms are used throughout as defined below.

As used herein and in the appended claims, singular articles such as “a”and “an” and “the” and similar referents in the context of describingthe elements (especially in the context of the following claims) are tobe construed to cover both the singular and the plural, unless otherwiseindicated herein or clearly contradicted by context. Recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate the embodiments and does not pose a limitation on the scopeof the claims unless otherwise stated. No language in the specificationshould be construed as indicating any non-claimed element as essential.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it also includes deuterium andtritium. Compounds comprising radioisotopes such as tritium, C¹⁴, P³²and S³⁵ are thus within the scope of the present technology. Proceduresfor inserting such labels into the compounds of the present technologywill be readily apparent to those skilled in the art based on thedisclosure herein.

The terms “pivaloyl”, “tosyl”, and “mesyl” will be understood by personsof ordinary skill in the art. However, to the extent one or more of suchterms are not clear to persons of ordinary skill in the art, the term“pivaloyl” refers to (CH₃)₃CC(O)—, the term “tosyl” refers to

and the term “mesyl” refers to

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 atoms refers to groupshaving 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers togroups having 1, 2, 3, 4, or 5 atoms, and so forth.

Pharmaceutically acceptable salts of compounds described herein arewithin the scope of the present technology and include acid or baseaddition salts which retain the desired pharmacological activity and isnot biologically undesirable (e.g., the salt is not unduly toxic,allergenic, or irritating, and is bioavailable). When the compound ofthe present technology has a basic group, such as, for example, an aminogroup, pharmaceutically acceptable salts can be formed with inorganicacids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuricacid, and phosphoric acid), organic acids (e.g., alginate, formic acid,acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid,tartaric acid, lactic acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (suchas aspartic acid and glutamic acid). When the compound of the presenttechnology has an acidic group, such as for example, a carboxylic acidgroup, it can form salts with metals, such as alkali and earth alkalimetals (e.g., Na⁺, Li⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺) ammonia or organic amines(e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine) or basic aminoacids (e.g., arginine, lysine and ornithine). Such salts can be preparedin situ during isolation and purification of the compounds or byseparately reacting the purified compound in its free base or free acidform with a suitable acid or base, respectively, and isolating the saltthus formed.

Those of skill in the art will appreciate that compounds of the presenttechnology may exhibit the phenomena of tautomerism, conformationalisomerism, geometric isomerism and/or stereoisomerism. As the formuladrawings within the specification and claims can represent only one ofthe possible tautomeric, conformational isomeric, stereochemical orgeometric isomeric forms, it should be understood that the presenttechnology encompasses any tautomeric, conformational isomeric,stereochemical and/or geometric isomeric forms of the compounds havingone or more of the utilities described herein, as well as mixtures ofthese various different forms.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The presence and concentrations of theisomeric forms will depend on the environment the compound is found inand may be different depending upon, for example, whether the compoundis a solid or is in an organic or aqueous solution. For example, inaqueous solution, quinazolinones may exhibit the following isomericforms, which are referred to as tautomers of each other:

As another example, guanidines may exhibit the following isomeric formsin protic organic solution, also referred to as tautomers of each other:

Because of the limits of representing compounds by structural formulas,it is to be understood that all chemical formulas of the compoundsdescribed herein represent all tautomeric forms of compounds and arewithin the scope of the present technology.

Stereoisomers of compounds (also known as optical isomers) include allchiral, diastereomeric, and racemic forms of a structure, unless thespecific stereochemistry is expressly indicated. Thus, compounds used inthe present technology include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions. Bothracemic and diastereomeric mixtures, as well as the individual opticalisomers can be isolated or synthesized so as to be substantially free oftheir enantiomeric or diastereomeric partners, and these stereoisomersare all within the scope of the present technology.

The compounds of the present technology may exist as solvates,especially hydrates. Hydrates may form during manufacture of thecompounds or compositions comprising the compounds, or hydrates may formover time due to the hygroscopic nature of the compounds. Compounds ofthe present technology may exist as organic solvates as well, includingDMF, ether, and alcohol solvates among others. The identification andpreparation of any particular solvate is within the skill of theordinary artisan of synthetic organic or medicinal chemistry.

The Present Technology

The historic synthesis of the “Corey lactones” (see Scheme 1; Corey, E.J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969,91, 5675) bearing contiguous stereocenters has powerfully enabled theenantioselective total synthesis of multiple prostaglandins, a family ofexceptionally bioactive molecules with hormone-like effects in animalsand humans. Since Corey revealed his chiral lactones in 1969, and withthe continuous discovery of novel bioactive natural products, thereexists an unsatisfied need for powerful synthetic tools that can enablesynthesis of such natural products on practical scales.

Over 10,000 polyketide natural products have been discovered to datewhere 1% of this number possesses desired biological activity.Nevertheless, this seemingly small fraction constitutes more than fivetimes the number from any other family of natural products therebypositioning polyketides as the ideal starting point for drug discovery.

A key feature of polyketide natural products is the existence of complexstereodefined arrays of contiguous stereocenters of alternating methyland hydroxyl groups known as “polypropionates”. In many instances, thenumber of contiguous stereocenters is four thus creating a“stereotetrad”. The synthetic obstacles of elaborating suchstereotetrads in a selective and enantiopure manner as well as provide asynthetic route with the flexibility and robustness to manufacture thesecomplex arrays on practical scale is a significant challenge.

The present technology is directed towards polypropionate lactonestereotetrads as valuable tools for many synthetic applications. Theseapplications include but not limited to processes such as lactoneopenings to termini-differentiated linear fragments, selectiveprotections, selective deprotections, reductions to aldehydes,reductions to lactols, olefination processes leading to cis and/or transolefins, olefination processes leading to E and/or Z-olefins, reductionsto alcohols, subsequent functionalization of primary alcohols includingbut not limited to iodinations, tosylations, organometallic formations,and subsequent couplings that involve carbon-carbon bond formations. Forexample, the polypropionate lactone stereotetrads of the presenttechnology may be utilized in the synthesis of Apyronine A as well asanalogues thereof, as illustrated in Hong, W. P. et al. “Synthesis ofthe C1-C20 and C15-C27 Segments of Aplyronine A” Org. Lett., 2011,13(24), 6342-6345, incorporated herein by reference.

Thus, in an aspect, a compound according to Formula I is provided

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

-   -   R¹ is H, trimethylsilyl (TMS), triethylsilyl (TES),        tert-butyl-dimethylsilyl (TBS), triisopropylsilyl (TIPS),        tert-butyl-diphenylsilyl (TBDPS), triphenylsilyl,        dimethylphenylsilyl, methyldiphenylsilyl, acetyl (Ac), pivaloyl        (Piv), trichloroacetyl, 2,2,2-trichloroethoxycarbonyl (Troc),        benzyl, p-methoxybenzyl (PMB), 3-(phenylsulfonyl)propionyl,        tosyl (Ts), or mesyl (Ms);    -   R² is H, TMS, TES, TBS, TIPS, TBDPS, triphenylsilyl,        dimethylphenylsilyl, methyldiphenylsilyl, Ac, Piv,        trichloroacetyl, Troc, benzyl, PMB, 3-(phenylsulfonyl)propionyl,        Ts, or Ms; and    -   n is 1 or 2;

provided that the compound of Formula I is not:

In any embodiment herein, it may be that the compound of Formula I isnot:

The compound of Formula I may be a compound of any one of FormulasI₁-I₁₆:

where R¹, R², and n are defined regarding Formula I.

In any embodiment herein, it may be that R¹ is TBS or acetyl. In anyembodiment herein, it may be that R² is triphenylsilyl. It may be thatthe compound of Formula I is a crystalline solid. As crystalline solids,this enables facile packaging, shipping, and weighing of such compounds.In addition, compounds where R¹ and/or R² include aromatic groups, e.g.,triphenylsilyl, are UV-active, allowing for facile monitoring ofreactions involving such compounds without the need for stainingtechniques. Exemplary compounds of Formula I include, but are notlimited to:

The examples herein are provided to illustrate advantages of the presenttechnology and to further assist a person of ordinary skill in the artwith preparing or using the compounds of the present technology. Theexamples herein are also presented in order to more fully illustrate thepreferred aspects of the present technology. The examples should in noway be construed as limiting the scope of the present technology, asdefined by the appended claims. The examples can include or incorporateany of the variations, aspects or aspects of the present technologydescribed above. The variations, aspects or aspects described above mayalso further each include or incorporate the variations of any or allother variations, aspects or aspects of the present technology.

Examples

Representative Synthetic Procedures

In addition to the procedures described in Hong, W. P. et al. “Synthesisof the C1-C20 and C15-C27 Segments of Aplyronine A” Org. Lett., 2011,13(24), 6342-6345, various representative synthetic procedures areillustrated below in Schemes 2-17.

Exemplary Syntheses of Certain Compounds of Present Technology

General Synthetic and Analytical Details:

All chemical reagents and dry solvents were purchased from commercialsuppliers and used without further purification. Unless otherwiseindicated, reactions were performed in dried standard glassware andunder an atmosphere of argon. ¹H was recorded a 300 MHz spectrometerusing tetramethyl silane as an internal standard. Chemical shifts (δ)are reported in ppm and coupling constants (J) are reported in Hz.

Example 1. Exemplary Crystalline Compound of the Present Technology

To a 50 mL round bottom flask was charged alcohol 1 (1.25 g, 4.14 mmol,1 equiv), Ph₃SiCl (1.336 g, 4.35 mmol, 1.05 equiv) and drydichloromethane (10 mL) under strict anhydrous conditions to give aclear and colorless solution. The solution was stirred at 23° C. for 5minutes, then 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”; 625 mL, 4.14mmol, 1 equiv) was added dropwise, and the resulting suspension wasstirred for 30-60 minutes. The reaction was diluted with hexane (10 mL),filtered through a pad of Celite®, and the filtrate was concentratedunder vacuum to give a crude yellow oil. Crystallization fromhexane-dichloromethane afforded 2 as white prisms (3.8 g, 92%). ¹H NMR(300 MHz, CDCl₃) δ 7.62-7.57 (m, 6H), 7.46-7.33 (m, 9H), 4.13-3.92 (m,2H), 3.87 (dt, J=3.0, 15.0 Hz, 1H), 3.62-3.58 (m, 1H), 2.36 (ddd, J=3.0,9.0, 15.0 Hz, 1H), 2.02-1.87 (m, 1H), 1.84-1.67 (m, 2H), 1.15 (d, J=6.0Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 0.83 (s, 9H), 0.01 (s, 6H). FIG. 1provides a photograph of crystals of 2 during crystallization.

Example 2. Exemplary One-Pot Elaboration of a Compound of the PresentTechnology

A 100 mL dry 3-neck flask was fit with a gas inlet adapter attached to agas dispersion tube, a drying tube, and an outlet to an aqueous 10%potassium iodide solution. The flask was charged with 3 (5.0 g, 12.18mmol, 1 equiv), pyridine (4.9 mL, 60.9 mmol, 5.0 equiv), and drydichloromethane (60 mL). The resulting solution was cooled to −40° C.,ozone was bubbled for 60 minutes, then purged with argon for 30 minutes.The solution was concentrated under vacuum, after which the resultingoil was dissolved in dichloromethane (30 mL). To this mixture TBSCl(5.67 g, 36.54 mmol, 3.0 equiv) was added followed by DBU (5.5 mL, 36.54mmol, 3.0 equiv). After 30 minutes, the yellow solution was cooled to−40° C., pyridine (4.9 mL, 60.9 mmol, 5.0 equiv) was added, and ozonewas bubbled for 60 minutes, then purged with argon for 30 minutes. Aftercooling for 30 minutes at 5° C., H₃B.^(t)BuNH₂ (1.59 g, 18.27 mmol, 1.5equiv) was added, and stirring was continued for 30 minutes. The organicphase was washed with 5% aqueous HCl (30 mL), saturated aqueous NaHCO₃(30 mL), dried with brine (30 mL), then with anhydrous sodium sulfate.The organic phase was filtered and concentrated under vacuum to give acrude brownish oil. Purification over a short silica pad affordedalcohol 4 as a pale yellow oil. (2.42 g, 69%). ¹H NMR (300 MHz, CDCl₃) δ4.83 (dt, J=3.0, 6.0 Hz, 1H), 4.16 (dd, J=5.4, 5.4 Hz, 1H), 2.87 (dd,J=8.9, 16.5 Hz, 1H), 2.77-2.69 (m, 1H), 2.63 (dd, J=4.8, 16.3 Hz, 1H),2.35-2.27 (m, 1H), 1.22 (d, J=7.2 Hz, 3H), 0.96 (d, J=7.2 Hz, 3H), 0.89(s, 9H), 0.06 (s, 3H), 0.06 (s, 3H).

Example 3. Exemplary Selective and Facile Deprotection of a PrimaryTriphenylsilyl Group in the Presence of a SecondaryTert-Butyldimethylsilyl Group

A 50 mL flask was charged with 2 (560 mg, 1 mmol, 1 equiv), methanol(2.0 mL), dichloromethane (10.0 mL), and the solution was cooled at 5°C. for 30 minutes. (+)-Camphorsulfonic acid (47.4 mg, 0.2 mmol, 0.2equiv) was added portionwise, and the solution was stirred for 30minutes. The reaction mixture was diluted with dichloromethane (20 mL),washed with saturated aqueous NaHCO₃ (20 mL), dried with brine (20 mL),then with anhydrous sodium sulfate. Filtration followed by concentrationunder vacuum gave crude yellow oil. Purification by filtration over ashort silica pad afforded 1 as a colorless oil (266 mg, 88%). Notably,the tert-butyldimethylsilyl group was fully intact under theseconditions, and the received product 1 represented 100% selectivity inthe removal of triphenylsilyl group in the presence of thetert-butyldimethylsilyl group. ¹H NMR (300 MHz, CDCl₃) δ 4.01 (dt,J=2.4, 9.6 Hz, 1H), 3.90 (dt, J=4.5, 10.8 Hz, 1H), 3.85 (dt, J=5.1, 10.8Hz, 1H), 3.68 (dd, J=2.1, 2.4 Hz, 1H), 2.63 (dq, J=3.3, 6.9 Hz, 1H),1.98 (dddd, J=2.4, 5.4, 8.1, 14.1 Hz, 1H), 1.85 (dt, J=4.8, 9.3 Hz, 1H),1.80 (dt, J=4.5, 9.3 Hz, 1H), 1.22 (d, J=6.6 Hz, 3H), 1.03 (d, J=7.2 Hz,3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).

It was consistently observed that 2 of Examples 1 and 3 is UV-activeunder UV-light 254/365 nm while 1 lacks any UV-activity. The UV-activityis an advantage as it provides facile reaction monitoring without theneed for special staining techniques. In addition, samples of 2 werestable at −20° C. for extended periods (months) without loss ofUV-activity or desilylation of the triphenylsilyl andtert-butyldimethylsilyl groups.

Example 4. Exemplary Synthesis of Further Crystalline Compounds of thePresent Technology

A 50 mL round bottom flask was charged with 5 (5.0 g, 12.18 mmol, 1equiv), dichloromethane (30 mL), pyridine (3.43 mL, 42.62 mmol, 3.5equiv), and 4-dimethylaminopyridine (150 mg, 1.218 mmol, 0.1 equiv).Acetic anhydride (3.45 mL, 36.54 mmol, 3.0 equiv) was added dropwise,and stirring was continued for 12 h. The organic phase was washed with5% aqueous HCl (30 mL), washed with saturated aqueous NaHCO₃ (30 mL),dried with brine (30 mL), and with anhydrous Na₂SO₄. Filtration followedby concentration in vacuum afforded a yellow crystalline solid.Recrystallization from hexane-dichloromethane afforded 6 as pale yellowcrystals (3.9 g, 95%). ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=8.1 Hz, 2H),7.59 (dt, J=1.5, 6.9 Hz, 1H), 7.50 (dt, J=1.5, 6.9 Hz, 2H), 7.16 (t,J=6.9 Hz, 1H), 5.27 (s, 1H), 4.95 (t, J=3.9 Hz, 1H), 3.74 (t, J=5.4 Hz,1H), 2.88 (ddd, J=3.9, 7.2, 14.4 Hz, 1H), 2.75 (dd, J=6.6, 15.9 Hz, 1H),2.61 (dt, J=7.2, 15.6 Hz, 1H), 2.00 (s, 3H), 1.13 (d, J=7.2 Hz, 3H),1.05 (d, J=6.9 Hz, 3H).

To a 100 mL dry 3-neck flask was fit with a gas inlet adapter attachedto a gas dispersion tube, a drying tube, and an outlet to 10% aqueouspotassium iodide solution. The flask was charged with 6 (2.0 g, 5.92mmol, 1 equiv; described above), pyridine (2.4 mL, 29.6 mmol, 5.0equiv), and dry dichloromethane (60 mL). The resulting solution wascooled to −40° C., ozone was bubbled for 60 minutes, then purged withargon for 30 minutes. The solution was concentrated under vacuum, theresulting oil was dissolved in dichloromethane (15 mL), and aceticanhydride (2.8 mL, 29.6 mmol, 5.0 equiv) was added followed by DBU (1.8mL, 11.84 mmol, 2.0 equiv). After 12 h, the yellow solution was cooledto −40° C., pyridine (2.4 mL, 29.6 mmol, 5.0 equiv) was added, and ozonewas bubbled for 60 minutes, then purged with argon for 30 minutes. Aftercooling for 30 minutes at 5° C., H₃B.^(t)BuNH₂ (773 mg, 8.88 mmol, 1.5equiv) was added, and stirring was continued for 30 minutes. The organicphase was washed with 5% aqueous HCl (30 mL), saturated aqueous NaHCO₃(30 mL), dried with brine (30 mL), then with anhydrous sodium sulfate.The organic phase was filtered and concentrated under vacuum to give acrude brown oil. Purification over a short silica pad afforded alcohol 7as pale yellow crystals (793 mg, 62%). ¹H NMR (300 MHz, CDCl₃) δ 4.92(dd, J=4.3, 5.2 Hz, 1H), 4.72 (dt, J=3.2, 4.8 Hz, 1H), 3.84-3.81 (2H,3.82 (d, J=4.9 Hz, 1H), 3.82 (d, J=4.9 Hz, 1H)), 2.70 (dq, J=5.2, 6.6Hz, 1H), 2.23-2.07 (4H, 2.15 (qdd, J=3.2, 4.3, 6.8 Hz, 1H, 1H, 2.07 (s,3H)), 1.24 (d, J=7.2 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H). FIG. 2 provides aphotograph of the crystals of 7.

While certain embodiments have been illustrated and described, a personwith ordinary skill in the art, after reading the foregoingspecification, can effect changes, substitutions of equivalents andother types of alterations to the compounds of the present technology.Each aspect and embodiment described above can also have included orincorporated therewith such variations or aspects as disclosed in regardto any or all of the other aspects and embodiments.

The present technology is also not to be limited in terms of theparticular aspects described herein, which are intended as singleillustrations of individual aspects of the present technology. Manymodifications and variations of this present technology can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. Functionally equivalent methods within thescope of the present technology, in addition to those enumerated herein,will be apparent to those skilled in the art from the foregoingdescriptions. Such modifications and variations are intended to fallwithin the scope of the appended claims. It is to be understood thatthis present technology is not limited to particular methods, reagents,compounds, compositions, labeled compounds or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only,and is not intended to be limiting. Thus, it is intended that thespecification be considered as exemplary only with the breadth, scopeand spirit of the present technology indicated only by the appendedclaims, definitions therein and any equivalents thereof.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group. Each of the narrowerspecies and subgeneric groupings falling within the generic disclosurealso form part of the invention. This includes the generic descriptionof the invention with a proviso or negative limitation removing anysubject matter from the genus, regardless of whether or not the excisedmaterial is specifically recited herein.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments (for example, journals, articles and/or textbooks) referred toin this specification are herein incorporated by reference as if eachindividual publication, patent application, issued patent, or otherdocument was specifically and individually indicated to be incorporatedby reference in its entirety. Definitions that are contained in textincorporated by reference are excluded to the extent that theycontradict definitions in this disclosure.

The present technology may include, but is not limited to, the featuresand combinations of features recited in the following letteredparagraphs, it being understood that the following paragraphs should notbe interpreted as limiting the scope of the claims as appended hereto ormandating that all such features must necessarily be included in suchclaims:

-   A. A compound of Formula I

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

-   -   R¹ is H, trimethylsilyl (TMS), triethylsilyl (TES),        tert-butyl-dimethylsilyl (TBS), triisopropylsilyl (TIPS),        tert-butyl-diphenylsilyl (TBDPS), triphenylsilyl,        dimethylphenylsilyl, methyldiphenylsilyl, acetyl (Ac), pivaloyl        (Piv), trichloroacetyl, 2,2,2-trichloroethoxycarbonyl (Troc),        benzyl, p-methoxybenzyl (PMB), 3-(phenylsulfonyl)propionyl,        tosyl (Ts), or mesyl (Ms);    -   R² is H, TMS, TES, TBS, TIPS, TBDPS, triphenylsilyl,        dimethylphenylsilyl, methyldiphenylsilyl, Ac, Piv,        trichloroacetyl, Troc, benzyl, PMB, 3-(phenylsulfonyl)propionyl,        Ts, or Ms; and    -   n is 1 or 2;

provided that the compound of Formula I is not

-   B. The compound of Paragraph A, wherein the compound of Formula I is    not

-   C. The compound of Paragraph A or Paragraph B, wherein R¹ is TBS or    acetyl.-   D. The compound of any one of Paragraphs A-C, wherein R² is    triphenylsilyl.-   E. The compound of any one of Paragraphs A-D, wherein the compound    of Formula I is a crystalline solid.-   F. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁

or a pharmaceutically acceptable salt and/or solvate thereof.

-   G. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₂

or a pharmaceutically acceptable salt and/or solvate thereof.

-   H. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₃

or a pharmaceutically acceptable salt and/or solvate thereof.

-   I. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₄

or a pharmaceutically acceptable salt and/or solvate thereof.

-   J. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₅

or a pharmaceutically acceptable salt and/or solvate thereof.

-   K. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₆

or a pharmaceutically acceptable salt and/or solvate thereof.

-   L. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₇

or a pharmaceutically acceptable salt and/or solvate thereof.

-   M. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₈

or a pharmaceutically acceptable salt and/or solvate thereof.

-   N. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₉

or a pharmaceutically acceptable salt and/or solvate thereof.

-   O. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁₀

or a pharmaceutically acceptable salt and/or solvate thereof.

-   P. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I_(ii)

or a pharmaceutically acceptable salt and/or solvate thereof.

-   Q. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁₂

or a pharmaceutically acceptable salt and/or solvate thereof.

-   R. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁₃

or a pharmaceutically acceptable salt and/or solvate thereof.

-   S. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁₄

or a pharmaceutically acceptable salt and/or solvate thereof.

-   T. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁₅

or a pharmaceutically acceptable salt and/or solvate thereof.

-   U. The compound of any one of Paragraphs A-E, wherein the compound    of Formula I is of Formula I₁₆

or a pharmaceutically acceptable salt and/or solvate thereof.

-   V. The compound of any one of Paragraphs A-U, wherein n is 1.-   W. The compound of any one of Paragraphs A-U, wherein n is 2.-   X. The compound of any one of Paragraphs A-U, wherein the compound    of Formula I is

Other embodiments are set forth in the following claims, along with thefull scope of equivalents to which such claims are entitled.

What is claimed is:
 1. A compound of any one of Formulas I₁, I₃, andI₁₂-I₁₆:

or a solvate thereof, wherein R¹ is independently at each occurrencetert-butyl-dimethylsilyl; R² is independently at each occurrencetriphenylsilyl; n is independently at each occurrence 1 or 2; andwherein the compound is a crystalline solid.
 2. The compound of claim 1,wherein the compound is of Formula I₁:

or a solvate thereof.
 3. The compound of claim 1, wherein the compoundis of Formula I₃:

or a solvate thereof.
 4. The compound of claim 1, wherein the compoundis of Formula I₁₂:

or a solvate thereof.
 5. The compound of claim 1, wherein the compoundis of Formula I₁₃:

or a solvate thereof.
 6. The compound of claim 1, wherein the compoundis of Formula I₁₄:

or a solvate thereof.
 7. The compound of claim 1, wherein the compoundis of Formula I₁₅:

or a solvate thereof.
 8. The compound of claim 1, wherein the compoundis of Formula I₁₆:

or a solvate thereof.
 9. The compound of claim 1, wherein the compoundis: